Repeated 2-deoxy-D-glucose-induced glucoprivation attenuates Fos expression and glucoregulatory responses during subsequent glucoprivation.

Abstract

A condition of reduced responsiveness to hypoglycemia, known as hypoglycemia-associated autonomic failure (HAAF), occurs in diabetic patients in the wake of a prior hypoglycemic episode. This condition suggests that hypoglycemia alters central glucose-sensing mechanisms. This experiment examined the effects of repeated 2-deoxy-D-glucose (2DG)-induced glucoprivation on subsequent 2DG-induced feeding and hyperglycemic responses in rats. Fos immunoreactivity (ir) in adrenal medulla and brain sites involved in these responses was also examined. Rats were injected daily for 10 days with 2DG (200 mg/kg) or saline (0.9%) or were handled. On day 11, rats were injected with 2DG (200 mg/kg). After injection, food intake was measured in one group. In another group, food was withheld, and multiple blood samples were collected for glucose determination. In a third group, food was withheld, and rats were killed after 2 h for evaluation of Fos-ir. Prior repeated glucoprivation reduced subsequent feeding and hyperglycemia responses to 2DG to baseline levels. Double-label immunohistochemistry showed that Fos-ir was reduced or abolished in catecholamine cell groups A1, A1/C1, C1, C3, and A6 and in the paraventricular nucleus of the hypothalamus and adrenal medulla. In other brain sites, 2DG-induced Fos-ir was diminished or unaffected by prior glucoprivation. Sites in which Fos-ir was abolished have been implicated previously in glucoprivic control of feeding and adrenal medullary secretion. Therefore, the present findings may identify crucial neuroanatomical sites that are altered by prior glucoprivation and that mediate some of the physiological deficits observed in HAAF.

Involvement of neuropeptide Y in glucose sensing in the dorsal hypothalamus of streptozotocin diabetic rats – in vitro and in vivo studies of transmitter release

“…Glucose sensing structures have also been reported in the caudal part of the NTS in the medulla [22], where K ATP channels have been pharmacologically identified [37]. Our data showed no significant effect of low glucose on NPY overflow in the dorsal medulla in both control rats and diabetic rats.…”

“…However, the characteristics of these neurons remain largely unknown. Several candidate transmitters are implicated in central glucose sensing, including some amino acids, catecholamines and neuropeptide Y (NPY) [19,22].…”

Increased GABAergic Tone in the Ventromedial Hypothalamus Contributes to Suppression of Counterregulatory Reponses After Antecedent Hypoglycemia

“…As recent antecedent hypoglycemia reduces autonomic (epinephrine) and symptomatic (which normally prompts behavioral defenses such as eating) responses to subsequent hypoglycemia (6,7), a vicious cycle of recurrent hypoglycemia is created where hypoglycemia leads to further impairment of counterregulatory responses, which in turn begets more hypoglycemia and so forth (4,8). Although several mechanisms have been proposed for the development of HAAF, including increased brain glucose transport (9 -11), changes in brain fuel metabolism (12)(13)(14), altered hypothalamic activity (15,16), and changes in brain glucose sensing and signaling (17,18), the exact mechanism underlying this phenomenon is unclear.…”

Effects of Repetitive Hypoglycemia on Neuroendocrine Response and Brain Tyrosine Hydroxylase Activity in the Rat

“…This is supported by the studies from Borg et al (1995; that demonstrate the direct infusion of the neuroglucopenic agent 2-deoxyglucose (2DG) into the ventromedial nucleus of the hypothalamus (VMH) results in activation of a neuroendocrine counter-regulatory response; and glucose infusion into the VMH can reverse the counter-regulatory response to peripherally-induced neuroglucopenia. Peripheral administration of 2DG can result in increased c-fos immunoreactivity in brainstem catecholamine neurons (an index of neuronal activation) in brainstem catecholaminergic neurons (Ritter and Dinh, 1994;Sanders and Ritter, 2000). Insulin-induced hypoglycemia has been reported not to result in increased c-fos expression in these neurons (Baffi et al, 1996).…”

“…This provides further evidence, with another marker of neuronal responsivity, that insulin hypoglycemia and neuroglucopenia may represent different stimuli to the CNS. Sanders and Ritter (2000) have recently reported that both brainstem c-fos activation and counter-regulatory responses to subcutaneous 2DG were blunted in animals pretreated with 10 daily injections of 2DG. This time course would allow for adaptive changes such as gene and protein expression in nerve terminals, or perhaps altered efficiency of glucose uptake by the CNS, as has been reported by Doyle et al (1995).…”